AUTONOMIC DRUGS:
ADRENOCEPTOR AGONISTS
AND SYMPATHOMIMETICS
Lecture 4
Introduction (review)

5 key features of neurotransmitter function, which
can be targets for pharmacotherapy
 Synthesis
 Storage
 Release
 Termination
of action
 Receptor effects
Sympathetic agents

MOA
 Direct
acting
 Directly
 Indirect
stimulate the receptor
acting
 Displace/release
stored catecholamines from the nerve (ex.
tyramine)
 Decrease clearance of NE by


Inhibiting reuptake of catecholamines (ex. cocaine and TCAs)
 By inhibiting NET (norepinephrine transporter)
 By altering NET to become a reverse transporter
Preventing the metabolism of NE (ex. MAO inhibitors)
Normal activity of NET
Blockage of NET by cocaine
Blockage of and reverse transport of
NET by amphetamine
MAO inhibitors
Sympathetic agents


NET EFFECT = increase NE activation or supply to
the receptors
Binding of agonist or drug to receptors
Sympathetic agents

MOA to the adrenoceptors
 Act
on G-protein coupled receptors, which then
activates the 2nd messenger system
 Receptor subtypes
 Alpha
 Beta
 Dopamine
Adrenoceptors
Receptor
Location
Alpha 1
Postsynaptic effector cells, especially smooth muscle
Alpha 2
Presynaptic adrenergic nerve terminals, platelets,
lipocytes, smooth muscle
Beta 1
Postsynaptic effector cells (heart, lipocytes, brain)
Presynaptic adrenergic and cholinergic nerve
terminals
Juxtaglumerular (JG) apparatus
Beta 2
Postsynaptic effector cells (smooth and cardiac
muscles)
D1
Brain, effector tissues, kidney vascular bed
D2
Brain, effector tissues, smooth muscles
Sympathetic agents

Alpha receptors
 alpha1
(α1)
 alpha2 (α2)

Beta receptors
 Beta1
(β1)
 Beta2 (β2)
 Beta3 (β3)

Dopamine receptors
 D1
 D2
Sympathetic agents

Selective
 Majority
of the drugs are selective (will preferentially
bind to a specific receptor). But as concentration
increases, the other receptors will also be stimulated.
 Ex.
 Phenylephrine
is a selective α1 agonist. If given at higher
doses, it may eventually stimulate α2 and even β receptors
at toxic doses.
Relative receptor affinities
Alpha agonists
Phenylephrine, methoxamine
α1 > α2 >>>>> β
Clonidine
α2 > α1 >>>>> β
Mixed alpha and beta agonists
Norepinephrine
α1 = α2; β1 >> β2
Epinephrine
α1 = α2; β1 = β2
Beta agonists
Dobutamine
β1 > β2 >>>> α
Isoproterenol
β1 = β2 >>>> α
Albuterol, terbutaline
β2 >> β1 >>>> α
Dopamine agonist (Dopamine)
D1 = D2 >> β >> α
Sympathetic agents

Receptor regulation
 More
for adrenoceptors than cholinoceptors
 Down regulation or desensitization
 There
will be less response to the agonist
 2 mechanisms


Slow desensitization (hours to days)
 Decrease in receptor production (down regulation)
Rapid desensitization (minutes)
 Decrease in function of a receptor thru phosphorylation
(rapid negative-feedback effect)
Sympathetic agents

Chemistry of catecholamines
 Basic
chemistry is that of phenylethylamine
Sympathetic agents
 Substitution
of H by OH at the 3 and 4 carbon atoms in
the benzene ring will produce the group Catecholamines
 Epinephrine,
Norepinephrine, Isoproterenol, Dopamine
 Further
substitutions or removal of OH among the
different carbon atoms will alter the characteristics of
the succeeding drugs.
 Non-catecholamines:
phenylephrine, methoxamine,
ephedrine, amphetamine
Catecholamines
Non-catecholamines
Catecholamines


Maximal alpha and beta activity
Inactivated by COMT (catechol-Omethyltransferase)
 Found
in the gut and liver = does not allow oral
administration of epi and norepi
 Absence of one or both OH groups on the phenyl ring

susceptibility to COMT   bioavailability after oral
adminstration   duration of action
  entry of drug to the CNS
 Ex. non-catecholamines = phenylephrine and amphetamine
Catecholamines

Alterations in the amine side-chain
 Increasing
the size of the amino group tends to increase
βreceptor activity, with corresponding decreased α
receptor activity (ex. NE  Epi  Isoproterenol)
Relative receptor affinities
Alpha agonists
Phenylephrine, methoxamine
α1 > α2 >>>>> β
Clonidine
α2 > α1 >>>>> β
Mixed alpha and beta agonists
NE
α1 = α2; β1 >> β2
Epi
α1 = α2; β1 = β2
Beta agonists
Dobutamine
β1 > β2 >>>> α
Isoproterenol
β1 = β2 >>>> α
Albuterol, terbutaline
β2 >> β1 >>>> α
Dopamine agonist (Dopamine)
D1 = D2 >> β >> α
Catecholamines and noncatecholamines
 Alterations
in the amine side-chain
at the αcarbon  blocks metabolism by
monoamine oxidase (MAO) =  duration of action
 Ex. Ephedrine and amphetamine
 Substitution
Sympathomimetic agents

General Effects
 Cardiovascular
 Compensatory
system
reaction by the parasympathetic system
 Alpha1



Arterial and venous vasoconstriction
Reflex response of HR
Skin, nasal mucosa and GIT vessels constrict
 Alpha2


Mild vasoconstriction
More prominent CNS effect = vasodilation and chronotropy =
BP
Sympathomimetic agents

General Effects
 Cardiovascular
 Beta



receptors
Heart = inotropy, chronotropy, dromotropy
Beta2 = vasodilation
Net effect = systolic but diastolic pressure
 Dopamine


system
receptors
D1 = Vasodilation of renal, splanchnic (GIT), coronary, cerebral
 Improve perfusion to kidneys = urine output
Dopamine activates beta receptors in the heart
Sympathomimetic agents

Noncardiac effects
 Lungs
= beta2 = bronchodilation
 Eye
 alpha

pupillary dilation and increase outflow of aqueous humor
 Beta

antagonism
Decrease aqueous humor production
 Genito-urinary
 Alpha


Increase urinary sphincter tone (improve continence)
Ejaculation and detumescence
Sympathomimetic agents

Noncardiac effects
 Fat
cells
 Beta2
= glycogenolysis and increase insulin secretion
 Beta3 = lipolysis
 Diabetogenic
 Potassium
 Beta2

= promote uptake of potassium into cells
Treatment for hyperK (salb, insulin, calcium)
 Renin
 Beta1
= increase secretion  blood volume  BP
Sympathomimetic agents

Noncardiac effects
 CNS
 Most
seen among non-catecholamines
 Increased alertness, attentiveness
 Elevation of mood, insomnia, euphoria and anorexia
Adrenoceptors - Functions
Type
Tissue location
Action
α1
Most vascular smooth muscle
Contraction
Pupillary dilator muscle
Contraction (dilates pupil)
Pilomotor smooth muscle
Erects hair
Prostate
Contraction
Heart
inotropy
Post synaptic CNS neurons
Probably multiple (BP)
Platelets
Aggregation
Adrenergic and cholinergic nerve
terminals
Inhibits transmitter release
Some vascular smooth muscle
Contraction
Fat cells
Inhibits lipolysis
α2
Type
Tissue location
Action
β1
Heart, juxtaglomerular cells
chronotropy and
inotropy
renin release
β2
Respiratory, uterine and vascular
smooth muscle
Smooth muscle
relaxation
Skeletal muscle
Potassium uptake
Human liver
Activates glycogenolysis
β3
Fat cells
lipolysis
D1
Smooth muscle
Dilates renal blood
vessels
D2
Nerve endings
Modulates transmitter
release
Sympathomimetic drugs
Endogenous
catecholamines
Receptor
activity
Effect
Epinephrine
α1 = α2; β1
= β2
Vasoconstrictor (except in muscles =
vasodilation)
inotropy, chronotropy in heart
Norepinephrine
α1 = α2; β1
>> β2
BP
+ Inotropy, chronotropy
Dopamine
D1 = D2 >>
β >> α
+ inotropy, chronotropy
Reward stimulus
renal perfusion
Sympathomimetic drugs
Direct Acting
Receptor
activity
Effect
Phenylephrine
α1 > α2
>>>>> β
Mydriasis, decongestant, slight inc
in BP
Methoxamine
α1 > α2
>>>>> β
Vasoconstriction and vagally
mediated bradycardia
α2 > α1
>>>>> β
BP.
Mild sedative
Alpha2 agonists
Clonidine,
methyldopa
Oxymetazoline α2 >>> α1
Isoproterenol
Topical decongestant (constrict
nasal mucosa)
β1 = β2 >>>> Vasodilator, with increase in
α
cardiac output with a fall in
diastolic pressure
Direct Acting
Receptor
activity
Effect
Beta agonists
Isoproterenol
β1 = β2 >>>> Vasodilator, with increase in
α
cardiac output with a fall in
diastolic pressure
Dobutamine
β1 > β2 >>>> CO with less reflex tachycardia
α
Sympathomimetic drugs
Mixed acting
Receptor
activity
Effect
Ephedrine
β1 > β2 >>>> Mild stimulant
α
Phenylpropanolam α1 > α2
>>>>> β
ine
Appetite suppressant
Cocaine
Affects pleasure centers
Uses

Treatment of acute hypotension
 Fluids




first before sympathomimetic agents
Temporary emergency management of complete
heart block
Drug induced cardiac stress test (dobutamine
injection)
Local vasoconstriction
Mucous membrane decongestants  rebound
hyperemia may follow.
Uses



Asthma
Anaphylaxis
Mydriatic agent
BREAK
Adrenoceptor Antagonists


Selectivity to a receptor depends on chemical structure
and dose
MOA

Alpha blockers
Reversible: ex. phentolamine, prazosin, labetalol
 Irreversible: covalent bond with receptor



Phenoxybenzamine
Beta blockers
Competitive antagonists
 Well absorbed orally, but generally of low bioavailability



Extensive 1st pass effect in the liver
Affected by Cytochrome P450 inducers and inhibitors
Adrenoceptor Antagonists
 Beta
blockers
 Average
half life of 3-10 hours
 Except esmolol = rapid effect and rapidly inactivated
(10min) = good for hypertensive crisis
Adrenoceptor Antagonists
Receptor Affinity
Alpha antagonists
Prazosin, terazosin, doxazosin
α1 >>>>α2
Phenoxybenzamine
α1 > α2
Phentolamine
α1 = α2
Yohimbine, tolazoline
α2 >> α1
Mixed antagonists
Labetalol, carvedilol
β1 = β2 ≥ α1 > α2
Beta antagonists
Metoprolol, acebutolol, alprenolol
atenolol, esmolol, nevibolol, etc.
β1 >>> β2
Propanolol, carteolol, pindolol, timolol
β1 = β2
Butoxamine
β2 >>> β1
Adrenoceptor Antagonists = Opposite
effect
Type
Tissue location
Action
α1
Most vascular smooth muscle
Contraction
Pupillary dilator muscle
Contraction (dilates pupil)
Pilomotor smooth muscle
Erects hair
Prostate
Contraction
Heart
inotropy
Post synaptic CNS neurons
Probably multiple (BP)
Platelets
Aggregation
Adrenergic and cholinergic nerve
terminals
Inhibits transmitter release
Some vascular smooth muscle
Contraction
Fat cells
Inhibits lipolysis
α2
Adrenoceptor Antagonists = Opposite
effect
Type
Tissue location
Action
β1
Heart, juxtaglomerular cells
chronotropy and
inotropy
renin release
β2
Respiratory, uterine and vascular
smooth muscle
Smooth muscle
relaxation
Skeletal muscle
Potassium uptake
Human liver
Activates glycogenolysis
β3
Fat cells
lipolysis
D1
Smooth muscle
Dilates renal blood
vessels
D2
Nerve endings
Modulates transmitter
release
Alpha Antagonists

Phenoxybenzamine
 Irreversible
alpha blocker
 Also blocks histamine, Ach, and 5HT receptors
 Reduces blood pressure when sympathetic tone is high
useful for pheochromocytoma
 ADR
 orthostatic
hypotension and tachycardia
 Nasal congestion and inhibition of ejaculation
Alpha Antagonists

Phentolamine
 Competitive
blocker of α1 and α2
 Vasodilation with direct and reflex tachycardia (due to
antagonism to α2 receptors)
 ADR: tachycardia, arrythmia
 Used for tx of pheochromocytoma
Alpha Antagonists

Prazosin, Terazosin and Doxazosin
blocker
 Vasodilation with minimal effect on the heart
 Relaxes prostate muscle (useful for BPH)
 Half life
 α1
Prazosin
Terazosin
Doxazosin
Half life (hours)
3
9-12
22
Beta Antagonists

Propanolol
 Non-selective
beta blocker
 Decreased chronotropy and inotropy
 Mild bronchoconstriction

Metoprolol, atenolol
 Selective
beta1 blocker
 Decreased chronotropy and inotropy
 Mild hypoglycemia and vasodilation
Beta Antagonist

Nebivolol
 Most

selective beta1 inhibitor
Esmolol
 Ultra
short acting beta1 selective antagonist
 Treatment for arrythmias, perioperative hypertension
and myocardial ischemia
Mixed Antagonists

Labetalol and carvedilol
 β1 = β2 ≥ α1 > α2
 Decreased
blood pressure, but with less reflex
tachycardia due to low alpha antagonism
Uses – Alpha blockers

Treatment for
 Pheochromocytoma
 Urinary

obstruction and BPH
Other uses (not drug of choice)
 Hypertensive
emergencies
 Chronic hypertension
 Peripheral vascular disease
 Erectile dysfunction
Uses – Beta blockers

Treatment for

Angina and following myocardial infarction


Heart arrythmias


Decrease work load and oxygen demand of heart
Regulate heart rate and heart conduction speed
Chronic heart failure

Decrease cardiac remodeling
Glaucoma
 Hypertension

Especially for patient with uncontrolled diabetes
 In combination with a diuretic and a peripheral vasodilator

Uses – Beta blockers

Treatment for
 Hyperthyroidism
 Sympathetic
(for Propanolol)
antagonism and decreased peripheral
conversion of T4 to T3 (more active to less active)
Precautions

Beta blockers
 Hypercholesterolemia
 May
increase LDL and decrease HDL
 Congestive

heart failure?
Beta2 blockers
 Patients
 Use
with asthma
another anti-hypertensive drug
 Patients
with diabetes and inadequate glucose reserves
lipolysis and glycogenolysis = available blood
glucose = may promote hypoglycemia
 Inhibits